Mads Andersen

Procalcitonin-guided interventions against infections to increase early appropriate antibiotics and improve survival in the intensive care unit: a randomized trial.

Objective:For patients in intensive care units, sepsis is a common and potentially deadly complication and prompt initiation of appropriate antimicrobial therapy improves prognosis. The objective of this trial was to determine whether a strategy of antimicrobial spectrum escalation, guided by daily measurements of the biomarker procalcitonin, could reduce the time to appropriate therapy, thus improving survival. Design:Randomized controlled open-label trial. Setting:Nine multidisciplinary intensive care units across Denmark. Patients:A total of 1,200 critically ill patients were included after meeting the following eligibility requirements: expected intensive care unit stay of ≥24 hrs, nonpregnant, judged to not be harmed by blood sampling, bilirubin <40 mg/dL, and triglycerides <1000 mg/dL (not suspensive). Interventions:Patients were randomized either to the “standard-of-care-only arm,” receiving treatment according to the current international guidelines and blinded to procalcitonin levels, or to the “procalcitonin arm,” in which current guidelines were supplemented with a drug-escalation algorithm and intensified diagnostics based on daily procalcitonin measurements. Measurements and Main Results:The primary end point was death from any cause at day 28; this occurred for 31.5% (190 of 604) patients in the procalcitonin arm and for 32.0% (191 of 596) patients in the standard-of-care-only arm (absolute risk reduction, 0.6%; 95% confidence interval [CI] −4.7% to 5.9%). Length of stay in the intensive care unit was increased by one day (p = .004) in the procalcitonin arm, the rate of mechanical ventilation per day in the intensive care unit increased 4.9% (95% CI, 3.0–6.7%), and the relative risk of days with estimated glomerular filtration rate <60 mL/min/1.73 m2 was 1.21 (95% CI, 1.15–1.27). Conclusions:Procalcitonin-guided antimicrobial escalation in the intensive care unit did not improve survival and did lead to organ-related harm and prolonged admission to the intensive care unit. The procalcitonin strategy like the one used in this trial cannot be recommended.

Clinical characteristics and major comorbidities in heart failure patients more than 85 years of age compared with younger age groups

Heart failure (HF) is increasingly prevalent among the growing number of elderly people, but not well studied. We sought to evaluate disease pattern and importance of prognostic factors among very elderly patients with HF.

Kidney failure related to broad-spectrum antibiotics in critically ill patients: secondary end point results from a 1200 patient randomised trial.

Objectives To explore whether a strategy of more intensive antibiotic therapy leads to emergence or prolongation of renal failure in intensive care patients. Design Secondary analysis from a randomised antibiotic strategy trial (the Procalcitonin And Survival Study). The randomised arms were conserved from the primary trial for the main analysis. Setting Nine mixed surgical/medical intensive care units across Denmark. Participants 1200 adult intensive care patients, 18+ years, expected to stay +24 h. Exclusion criteria: bilirubin >40 mg/dl, triglycerides >1000 mg/dl, increased risk from blood sampling, pregnant/breast feeding and psychiatric patients. Interventions Patients were randomised to guideline-based therapy (‘standard-exposure’ arm) or to guideline-based therapy supplemented with antibiotic escalation whenever procalcitonin increased on daily measurements (‘high-exposure’ arm). Main outcome measures Primary end point: estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2. Secondary end points: (1) delta eGFR after starting/stopping a drug and (2) RIFLE criterion Risk ‘R’, Injury ‘I’ and Failure ‘F’. Analysis was by intention to treat. Results 28-day mortality was 31.8% and comparable (Jensen et al, Crit Care Med 2011). A total of 3672/7634 (48.1%) study days during follow-up in the high-exposure versus 3016/6949 (43.4%) in the ‘standard-exposure arm were spent with eGFR <60 ml/min/1.73 m2, p<0.001. In a multiple effects model, 3 piperacillin/tazobactam was identified as causing the lowest rate of renal recovery of all antibiotics used: 1.0 ml/min/1.73 m2/24 h while exposed to this drug (95% CI 0.7 to 1.3 ml/min/1.73 m2/24 h) vs meropenem: 2.9 ml/min/1.73 m2/24 h (2.5 to 3.3 ml/min/1.73 m2/24 h)); after discontinuing piperacillin/tazobactam, the renal recovery rate increased: 2.7 ml/min/1.73 m2/24 h (2.3 to 3.1 ml/min/1.73 m2 /24 h)). eGFR <60 ml/min/1.73 m2 in the two groups at entry and at last day of follow-up was 57% versus 55% and 41% versus 39%, respectively. Conclusions Piperacillin/tazobactam was identified as a cause of delayed renal recovery in critically ill patients. This nephrotoxicity was not observed when using other beta-lactam antibiotics. Trial registration ClinicalTrials.gov identifier: NCT00271752.

Profound endothelial damage predicts impending organ failure and death in sepsis.

Endothelial damage contributes to organ failure and mortality in sepsis, but the extent of the contribution remains poorly quantified. Here, we examine the association between biomarkers of superficial and profound endothelial damage (syndecan-1 and soluble thrombomodulin [sTM], respectively), organ failure, and death in sepsis. The data from a clinical trial, including critically ill patients predominantly suffering sepsis (Clinicaltrials.gov: NCT00271752) were studied. Syndecan-1 and sTM levels at the time of study enrollment were determined. The predictive ability of biomarker levels on death and organ failures during follow-up were assessed in Cox models adjusted for potential confounders including key organ dysfunction measures assessed at enrollment. Of the 1,103 included patients, 418 died. sTM levels at the time of enrollment independently predicted risk of death in adjusted models (hazard ratio [HR] [highest quartile > 14 ng/mL vs. lowest quartile < 7 ng/mL] 2.2 [95% confidence interval [CI]: 1.2-4.0], p = 0.02, respectively). Conversely, syndecan-1 levels failed to predict death (adjusted HR [> 240 vs. < 70 ng/mL] 1.0 [95% CI: 0.6-1.5], p = 0.67). sTM but not syndecan-1 levels at enrollment predicted risk of multiple organ failure during follow-up (HR [> 14 ng/mL vs. < 7 ng/mL] 3.5 [95% CI: 1.5-8.3], p = 0.005 and 2.0 [95% CI: 0.8-5.0], p = 0.1321, respectively). Profound damage to the endothelium independently predicts risk of multiple organ failure and death in septic patients. Our findings also suggest that the detrimental effect of profound endothelial damage on risk of death operates via mechanisms other than causing organ failures per se. Therefore, damage to the endothelium appears centrally involved in the pathogenesis of death in sepsis and could be a target for intervention.

Global left ventricular longitudinal strain is closely associated with increased neurohormonal activation after acute myocardial infarction in patients with both reduced and preserved ejection fraction: a two‐dimensional speckle tracking study

N‐terminal pro brain natriuretic peptide (NT‐proBNP) is released in response to increased myocardial wall stress and is associated with adverse outcome in acute myocardial infarction. However, little is known about the relationship between longitudinal deformation indices and NT‐proBNP.

Invasive Candida infections and the harm from antibacterial drugs in critically ill patients: data from a randomized, controlled trial to determine the role of ciprofloxacin, piperacillin-tazobactam, meropenem, and cefuroxime.

Objective:Use of antibiotics in critically ill patients may increase the risk of invasive Candida infection. The objective of this study was to determine whether increased exposure to antibiotics is associated with increased prevalence of invasive Candida infection. Design:Substudy using data from a randomized controlled trial, the Procalcitonin And Survival Study 2006–2010. Setting:Nine multidisciplinary ICUs across Denmark. Patients:A total of 1,200 critically ill patients. Intervention:Patients were randomly allocated to either a “high exposure” antibiotic therapy (intervention arm, n = 604) or a “standard exposure” guided by current guidelines (n = 596). Measurements and Main Results:Seventy-four patients met the endpoint, “invasive Candida infection,” 40 in the high exposure arm and 34 in standard exposure arm (relative risk = 1.2; 95% CI, 0.7–1.8; p = 0.52). Among medical patients in the high exposure arm, the use of ciprofloxacin and piperacillin/tazobactam was 51% and 75% higher than in the standard exposure arm; no difference in antibiotic exposure was observed between the randomized arms in surgical patients. Among medical intensive care patients, invasive Candida infection was more frequent in the high exposure arm (6.2%; 27/437) than in standard exposure arm (3.3%; 14/424) (hazard ratio = 1.9; 95% CI, 1.0–3.6; p = 0.05). Ciprofloxacin used at study entry independently predicted invasive Candida infection (adjusted hazard ratio = 2.1 [1.1–4.1]); the risk gradually increased with duration of ciprofloxacin therapy: six of 384 in patients not exposed (1.6%), eight of 212 (3.8%) when used for 1–2 days (hazard ratio = 2.5; 95% CI, 0.9–7.3), and 31 of 493 (6.3%) when used for 3 days (hazard ratio = 3.8; 95% CI, 1.6–9.3; p = 0.002). Patients with any ciprofloxacin-containing antibiotic regimen the first 3 days in the trial had a higher risk of invasive Candida infection than did patients on any antibiotic regimen not containing ciprofloxacin (unadjusted hazard ratio = 3.7; 95% CI, 1.6–8.7; p = 0.003; adjusted hazard ratio, 3.4; 95% CI, 1.4–8.0; p = 0.006). Conclusions:High exposure to antibiotics is associated to increased risk of invasive Candida infection in medical intensive care patients. Patients with ciprofloxacin-containing regimens had higher risk of invasive Candida infection. Other antibiotics, such as meropenem, piperacillin/tazobactam, and cefuroxime, were not associated with such a risk.

Long-term effect of epirubicin on incidence of heart failure in women with breast cancer: insight from a randomized clinical trial: Long-term effect of epirubicin on heart failure

Anthracycline‐based chemotherapy improves survival in breast cancer patients but is associated with increased risk of heart failure (HF). However, the risk of late‐onset HF is debatable and mainly based on observational studies. The aim of this study was to evaluate the effect of anthracycline‐based chemotherapy on long‐term risk of clinical HF.

Hemodynamic Characteristics in Significant Symptomatic and Asymptomatic Primary Mitral Valve Regurgitation at Rest and During Exercise

Background— In severe asymptomatic primary mitral valve regurgitation without risk factors, surgery strategy is controversial. We sought to clarify whether being symptomatic corresponds to the hemodynamic burden and reduced exercise capacity. A better understanding of this may contribute to optimize timing of surgery. Methods and Results— Subjects with asymptomatic (New York Heart Association functional class I, n=29) or symptomatic (New York Heart Association functional class II and III, n=28) significant primary mitral valve regurgitation (effective regurgitant orifice, ≥0.30 cm2; left ventricular ejection fraction, >60%) were included. Right heart catheterization during rest and exercise, echocardiography, magnetic resonance imaging, and peak oxygen consumption test was performed. Symptomatic subjects had significantly higher pulmonary capillary wedge pressure at rest (14±4 versus 11±3 mm Hg; P=0.003) and at maximal exercise (30±6 versus 25±7 mm Hg; P=0.02) and higher mean pulmonary artery pressure (PAP) at rest (22±7 versus 18±4 mm Hg; P=0.005) and maximal exercise (46±8 versus 39±7 mm Hg; P=0.005) than asymptomatic subjects. Among asymptomatic subjects with normal resting value, exercise testing revealed a systolic PAP >60 mm Hg in 34%. Also the reverse response with minimal increase in pulmonary capillary wedge pressure and mean PAP during exercise was seen, especially in asymptomatic subjects. Among symptomatic subjects, we found a significant inverse correlation between resting mean PAP and left ventricular ejection fraction (r=−0.52; P=0.02) and right ventricular ejection fraction (r=−0.67; P<0.01). Peak oxygen consumption was equal and normal in both groups and correlated with left ventricular stroke volume but not with pulmonary capillary wedge pressure. Conclusions— Symptoms in patients with severe mitral valve regurgitation relate to congestion (pulmonary capillary wedge pressure and PAP), but not to peak oxygen consumption, which is determined by forward left ventricular stroke volume. Exercise testing reveals a higher mitral valve regurgitation burden in apparently asymptomatic patients. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02961647.

Prolonged hyperthermia from furosemide infusion—a case report

Drug-induced side effects may complicate the picture in severely sick patients in the intensive care unit (ICU) treated with multiple drugs and with several affected organ systems. Presented here is a case where prolonged hyperthermia was suspected to be induced by intravenously administered furosemide. An 18-year-old girl suffered from verified severe Mycoplasma pneumoniae infection with complicating pulmonary hypertension, pronounced cryoglobulinaemia and rhabdomyolysis. The patient was mechanically ventilated, sedated and required haemodialysis for several weeks at the ICU. At the age of 2 weeks the patient had had surgical treatment of congenital aortic coarctation. She had an asymptomatic mitral stenosis and received no medication. The Mycoplasma infection was treated successfully with intravenous clarithromycin supplemented with meropenem. By day 19, the temperature and C-reactive protein (CRP) (Fig. 1) had normalised, and the cryoglobulins had disappeared by day 27. At day 24 the patient developed a second episode of hyperthermia (Fig. 1), without a concurrent increase in CRP. Simultaneously, the patient developed dermal blisters, histologically described as oedema with modest lymphocytic inflammation without eosinophilia. The patient was persistently hyperthermic and exhaustive investigation failed to detect ongoing infection. During this hyperthermia period, the patient was continuously infused with furosemide, remifentanil and actrapid. Moreover, treatment consisted of meropenem and methylprednisolone (iv), esomeprazole and paracetamol, and dalteparin (Fig. 1). To exclude drug-induced side effects, furosemide, dalteparin and esomeprazole were discontinued on day 29. Within 2 days the temperature and heart rate declined, and the skin manifestations vanished. The patient was rechallenged with two doses of furosemide 5 mg iv on day 32, which triggered an almost simultaneous increase in heart rate and temperature (Fig. 1 inset) and caused the blisters to reappear. After discontinuation of furosemide, all three symptoms quickly faded. Meropenem, esomeprazole and dalteparin were reintroduced later and were all well-tolerated. The authors declare that they have no conflicts of interest.